17alpha-alkyl-17beta-methyl-8xi, 9xi, 13xi, 14xi-gona-1,3,5(10)-trien-3-ols and conge



United States Patent 3,407,219 17a-ALKYL-17B-METHYL-8E,9,l3E,14E-GONA-l,3,5()-TRIEN-3-0LS AND C(JNGENERS Leland J. Chinn, Morton Grove, Ill.,assignor to G. D.

Searle & Co., Chicago, 111., a corporation of Delaware No Drawing. FiledDec. 22, 1965, Ser. No. 515,734 8 Claims. (Cl. 260-3975) This inventionrelates to 17a-alkyl-17,8-methyl-8g95, 13,14-gona-1,3,5(10)-trien-3-olsand congeners, and to processes for the preparation thereof. Moreparticularly, this invention provides new, useful, and unobvioussteroids of the formulas wherein Z represents hydrogen or an alkyl oraralkyl radical. Among the alkyl radicals called for, especiallyloweralkyl radicals are preferred, which is to say methyl, ethyl,propyl, isopropyl, butyl, isobutyl, sec-butyl, tertbutyl, pentyl,neopentyl, hexyl, isohexyl, heptyl, and like monovalent, saturated,acyclic straight-or branched-chain, hydrocarbon moieties of the formulan 2n+1 in which n represents a positive integer less than 8. The aralkylradicals represented by Z are preferably benzyl, phenylcthyl, and thelike, in which the phenyl constituent can be substituted by one or morelower alkyl, halogen, and/ or lower alkoxy radicals.

The compounds to which this invention relate are useful by reason oftheir valuable pharmacological properties. For instance, they reduce thefecundity of rodents, inhibit dicotyledonous seed germination,counteract infiammatory edema, depress the central nervous system, andare anti-gonadotropic.

Preparation of the subject compounds proceeds via the corresponding17w-a1klyl-1%p hydroxy-13-methyl-&p, 9a,l3fi,14a steroid. Thus, theappropriate phenolic ether orrao can be reduced with lithium in liquidammonia to the corresponding dienolic ether 3,407,219 Patented Oct. 22,1968 which, upon acidification with mineral acid, affords the 4-en-3-oneEither of the latter two compounds, upon heating with pyridinehydrochloride or hydrobromide, aifords the17malkyl-17/3-methyl-8,9g,135,14-gona-1,3,5(10)-trien-3 01.

The 3-0], in turn, is converted to the 3-ether by contact with anappropriate alkyl or aralkyl halide or sulfate in the presence of strongbase. The l7a-alky1-l7fl-methyl- 13,14-gona-1,3,5(10),8-tetraen-3-olshereof are obtained directly from the aforesaid phenolic ether startingmaterials by heating them with pyridine hydrohalide, and can beetherified by the same procedures which apply to their 8,9-dihydroanalogs.

The following examples described in detail compounds illustrative of theinvention and methods which have been devised for their preparation.However, the invention is not to be construed as limited thereby, eitherin spirit or in scope, since it will be apparent to those skilled in theart of organic synthesis that many modifications, both of materials andof methods, may be practiced without departing from the purpose andintent of this disclosure. Throughout the examples hereinafter setforth, temperatures are given in degrees centigrade and relative amountsof materials in parts by weight, except as otherwise noted.

EXAMPLE 1 17a,17fi-dimethyl-8,9, 1 3g, l4g-gona-1 ,3,5 10) trien-3-ol Amixture of 3 parts of l7 9-hydroxy-l7u-methylestr-4- en-3-one and 15parts of pyridine hydrochloride is heated at 235- 5 under nitrogen for 1/2 hours, then cooled and diluted with parts of water. The resultantmixture is chilled. Insoluble solids are filtered off, washed withwater, dried in air, and recrystallized from a mixture of ether andhexane to give 17u,17y8-dimethyl-8,9,13.5,145-gona- 1,3,5(10)-trien-3-olas colorless laths melting at 184.5- 187. The product has the formula OHH z EXAMPLE 2 solid potassium hydroxide is thereupon introduced, and themixture thus obtained is maintained at room temperatures with agitationfor a further 1 /2 hours. At this point, 1000 parts of water isintroduced; and the alcohol is-then removed by distillation undernitrogen at around 90. The residue is extracted with ether. The etherextract is washed with water and stripped of solvent by vacuumdistillation. The residue is steam distilled until the distillate isclear, whereupon it is extracted with ether. The extract is washed withwater, dried over anhydrous sodium sulfate, and stripped of solvent byvacuum distillation to afford a viscous oil as the residue. The oilcrystallizes from hexane as colorless plates melting at 93-98.5. Theproduct thus obtained is 3-benzyloxy-l7a,17 3-dimethyl-85,95,13.5,14-gona-1,3,5(10) -triene having the formula Q-cmo EXAMPLE 317a-ethyl-17fi-methyl-8,9g,-l 3.5, 14-gona-'1,3,5 10) trien-3-o1 Amixture of 100 parts of 17a-ethyl-l7p-hydroxyestr- 4-en-3-one and 485parts of pyridine hydrochloride is heated at 240 under nitrogen for 1 /2hours. The mixture is thereupon cooled and extracted with ether. Theether extract is washed with water, dried over anhydrous sodium sulfate,and stripped of solvent by vacuum distillation. The residue is taken upin hexane; and the resultant solution is chromatographed on silica gel,using hexane, benzene, and ethyl acetate as developing solvents. From aneluate comprising 50% benzene in hexane, on distillation of solvent andrecrystallization of the residue from hexane, is obtained17a-ethyl-l7fl-methyl-8,9,13, 14-gona- 1,3,5 10) -triene-3-ol ascolorless plates melting at approximately 152153.5. The product has theformula CH3 H 1....

H HO EXAMPLE 4 A mixture of 22 parts of 17 a-ethyl-3-methoxyestra-2,5(10)-dien-'17/3-ol and 100 parts of pyridine hydrochloride is heatedat 230-235 under nitrogen for 1% hours, then worked up as detailed inExample 3. The 17a-ethyl- 17fi-methyl-8,'9,13,14-gona-1,3,5(10)-trien 301 thus isolated melts at approximately 153.5-154.

EXAMPLE 5 17 a-ethyl-3-methoxy-17fi-methyl-8g9g,135,145-gona- 1,3,5('10)-triene To a solution of approximately 21 parts of 17a-ethyl-17,B-methyl-8,9,13, 14-gona l,3,5(10)-trien-3-ol in 400 parts of methylalcohol is added, with agitation at room temperature, approximately 200parts of a solution of potassium hydroxide prepared by dissolving 200parts of 85% potassium hydroxide in 400 parts of methyl alcohol and 200parts Of Water. There is then introduced, portionwise and alternatelyduring 10 minutes with continued agitation, 390 parts of dimethylsulfate and the balance of the aqueous alcoholic solution of potassiumhydroxide. Next, 19 parts of solid potassium hydroxide is incorporated,and the resultant mixture is maintained with further agitation at roomtemperatures for 16 hour. The mixture is thereupon diluted withapproximately 2 volumes of water, and the mixture thus obtained isextracted with ether. The ether extract is succesively washed with waterand saturated brine, dried over anhydrous sodium sulfate, and strippedof solvent by vacuum distillation. The residual oil, upon triturationwith methyl alcohol, affords 17a ethyl 3-methoxy-17;3-methyl-8,9,135,145-gona- 1,3,5 (10)-triene as colorlesscrystals which, recrystallized from a mixture of ether and methylalcohol, are obtained as colorless prisms melting at approximately71-72. The product has the formula EXAMPLE 617u-17p-dimethyl-13,14g-gona-1,3,5'(10)-8-tetraen-3-ol A mixture of '3parts of 3-methoxy-17a-methylestral,3,5(10)-trien-17/3-ol and 15 partsof pyridine hydrochloride is heated at 230:5" under nitrogen for 1 hour.The resultant mixture is cooled to room temperature, diluted with partsof water, and then chilled. Insoluble solids are filtered off, washedwith water, dried in air, and chromatographed on silica gel, usinghexane, benzene, and ethyl acetate as developing solvents. From aneluate comprising 10% hexane in benzene, upon evaporation of solvent andrecrystallization of the residue from a mixture of ether and hexane,17a,173-dimethyl-13,14gona-l,3,5 -(10),8-tetraen-3-ol is obtained ascolorless plates melting at 186-1875". The product has the formulaEXAMPLE 7 3-methoxy-17a,17;8-dimethyl-13,14-gona- 1,3,5 10),8-tetraeneTo a mixture of 66 parts of 17a,l7fl-dimethyl-l3,l4-gona-1,3,5(10),8-tetraen-3'ol and 1200 parts of methyl alcohol is added,with agitation at room temperature, ap proximately 1000 parts of asolution of potassium hydroxide prepared by dissolving 1000 parts ofpotassium hydroxide in 2000 parts of methyl alcohol and 1000 parts ofwater. There is then introduced, portionwise and alternately withcontinued agitation, .1950 parts of dimethyl sulfate and the balance ofthe aqueous alcoholic potassium hydroxide solution. Finally, 100 partsof solid potassium hydroxide is mixed in, and agitation at roomtemperatures is continued thereafter for 1 hour. The resultant mixtureis diluted with 10 volumes of water and chilled. The insoluble solidsthrown down are filtered off, washed well with water, dried in air, andcrystallized from a mixture of ether and methyl alcohol to give 3-methoxy-17a,l7 3-dimethyl 135,145 gona-1,3,5(10),8-

tetraene as colorless plates melting at approximately 121. The producthas the formula CH3 H I...

CHQO

EXAMPLE 8 CH2 H EXAMPLE 9 l7a-ethyl-3-methoxy-17fi-methyl-135,145-gona-1,3,5 10) ,-8-tetraene To a mixture of 27 parts of l7a-ethyl-l7flmethyl- 13z3,14-gona-1,3,5 (10),-8-tetraen-3-ol and 500 parts ofpotassium hydroxide in 1000 parts of water near the boiling point isadded, portionwise with agitation, 1300 parts of dimethyl sulfatefollowed by a solution of 500 parts of potassium hydroxide in 1000 partsof water. The resultant mixture is allowed to stand at room temperaturesfor 1 hour, whereupon it is diluted with 10,000 parts of water and themixture thus obtained chilled to The insoluble solids are filtered off,washed well with water, dried in air, and crystallized from pentane togive 17a-ethyl-3-methoxy-17B-methyl-13g145-gona 1,3,5(), S-tetraene ascolorless plates melting at 935-95". The product has the formula CHsO 6What is claimed is: 1. A compound selected from the group consisting ofcompounds of the formula OH H a --lower alkyl H HI R O and A compoundsotherwise identical, R in the formula being selected from the groupconsisting of hydrogen, benzyl, and lower alkyl, and the configurationof said compounds at all annular centers of asymmetry in the steroidring system being identical with that which characterizes compoundsprepared by heating a 17 fl-hydroxyl7oc-(lOWC1 alkyl)est-r-4-en-3-onewith pyridine hydrochloride.

2. A compound according to claim 1 having the formula ""lower alkyl 3. Acompound according to claim 1 which is :,175-dimethyl-8g,9g,13,14-gona-l,3,5 l0) ,8-trien-3-ol.

4. A compound according to claim 1 which is 17methyl-17fi-methyl-8g9g,1355, Magma-1,3,5 10) -trien-3-ol.

5. A compound according to claim 1 having the formula 6. A compoundaccording to claim 1 which is 1711,173- dimethyl-l3,14-gona-1,3,5( l0),-8-tetraen-3-ol.

7. A compound according to claim 1 having the formula H 'lower alkyllower alkyl-O 8. A compound according to claim 1 which is 3-mo- 5thoxy-17,17p-dimethyl-13g14-gona-1,3,5 10) ,S-tetraene,

No references cited.

HENRY FRENCH, Primary Examiner.

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF COMPOUNDS OF THEFORMULA